The present invention is directed to methods of treating vascular inflammatory pathologies such as atheroslcerosis and stroke. In particular, the invention is directed to the use of certain compounds having potent anti-inflammatory and anti-oxidant activity.
Free radical molecules play a major role in inflammation and other tissue pathology. These unstable chemical moieties cause the oxidation of biomolecules which can result in tissue damage. Such oxidative stress and damage has been described in Biochemical Pharmacology, volume 32(14), pages 2283-2286 (1983) and Free Radicals in Biology and Medicine, volume 4, pages 225-261 (1988). Agents that act as anti-oxidants can protect against oxidative damage. Such protection has been the subject of numerous scientific publications, including the following:
Archives of Pharmacology, volume 325, pages 129-146 (1992); PA1 Journal of Photochemistry and Photobiology, volume 8, pages 211-224 (1991); PA1 Free Radicals in Biology and Medicine, volume 11, pages 215-232 (1991); and PA1 European Journal of Pharmacology, volume 210, pages 85-90 (1992). PA1 Ophthalmoscope, volume 8, page 257 (1910); PA1 FASEB Journal, volume 1, page 89 (1987); and PA1 Inflammation and Mechanisms and Actions of Traditional Drugs, Vol. I Anti-inflammatory and Anti-rheumatic drugs. Boca Raton, Fla., CRC Press, (1985).
Oxidation of various biomolecules in the vasculature has been implicated in numerous cardiovascular pathologies including atherosclerosis, thrombosis, myocardial infarction and congestive heart failure. In particular, several reports demonstrate a correlation between the oxidation of low-density lipoproteins (LDL) and the progression of atherosclerotic lesions (New England Journal of Medicine, volume 328(20), pages 1444-1449 (1993)). These oxidized LDLs have been further characterized in several pathological events including: 1) chemotaxis, which draws monocytes to the afflicted tissue; 2) differentiation of monocytes into macrophages; 3) uptake of LDL by macrophages to form foam cells; 4) proliferation of smooth muscle cells; 5) development of atherosclerotic lesions; and 6) cytotoxic effects on endothelial cells as well as increases in arterial vasoconstriction (JAMA, volume 264(3), pages3047-3052 (1990)).
The use of antioxidants to ameliorate coronary heart disease has been explored. Epidemiological studies have correlated the dietary intake of Vitamin E with reduced risk to coronary heart disease (New England Journal of Medicine, volume 328(20), pages 1444-1449 (1993); and New England Journal of Medicine, volume 328 (20), pages 1450-156 (1993)). .beta.-carotene, a naturally occuring anti-oxidant, has been pursued in the clinic for cardiovascular disease indications (Scrip No., 1574:31 (1990)). Additionally, research has shown that treatment of hypercholesterolemic animals with antioxidant drugs, including the phenolic antioxidant compound, probucol, has reduced the development of atherosclerosis (Proceedings of the National Academy of Science, U.S.A., volume 84, pages 7725-7729 (1989)).
Oxygen radicals have also been implicated in the pathogenesis of a number of other inflammatory conditions. Such conditions have included stroke, rheumatoid arthritis, retinopathy and endotoxic liver injury. It is believed that anti-oxidants would be useful in treating such conditions (Methods in Enzymology, volume 186, pages 1-85 (1990)).
Inflammation from cellular stress can also cause excessive tissue damage. Numerous biochemical pathways are known to lead to inflammation. In general, the cyclooxygenase system produces prostaglandins, while the lipoxygenase system produces leukotrienes, "HETEs" and "HPETEs." See generally, Goodman and Gilman's The Pharmacological Basis of Therapeutics, pages 600-617, Pergman Press, NY (1990). Therapies designed to inhibit the production of these types of agents are therefore of great interest.
Anti-inflammatory therapy has been suggested as an adjuvant to the treatment of various cardiovascular indications. These agents assist in preventing thrombotic and atherosclerotic occlusions and restenosis of the vasculature by inhibiting platelet and leukocyte aggregation. Non-steroidal anti-inflammatory agents (NSAIA) have been used for the treatment of inflammatory disorders. The following references may be referred to for further background concerning this use of NSAIAs:
As such, aspirin has been prescribed broadly, for anti-inflammatory and analgetic indications, as well as for patients with unstable angina. Ibuprofen and naproxen have been prescribed for treatment of rheumatoid arthritis and moderate pain. However, there are some problems associated with NSAIA treatment including delivery to the appropriate site of action and side effects (Goodman and Gilman's The Pharmacological Basis of Therapeutics, pages 638-669, Pergroan Press, NY (1990)).
The combination of anti-oxidant activity with other pharmacologically significant activities in a single molecule is discussed in JP 64-40484 and EP 387771 A2; and compounds with cyclooxygenase/5-lipoxygenase and anti-oxidant activity are discussed in Drug Research, volume 39(II) number 10, pages 1242-1250 (1989). However, these references do not disclose the compounds of the present invention.
The present invention is directed to methods for the prevention and amelioration of oxidative and/or inflammatory pathologies in mammals. The methods of the present invention utilize compositions containing novel compounds that have both potent anti-inflammatory activity and potent anti-oxidant activity in a single molecule. The use of a single chemical entity with potent anti-inflammatory and potent anti-oxidant activity provides increased protection relative to the use of a compound with singular activity. The use of a single agent having both activities over a combination of two different agents provides uniform delivery of an active molecule, thereby simplifying issues of drug metabolism, toxicity and delivery.